A large body of recently accumulated evidence indicates that type I diabetes mellitus results from a slowly progressive, immunologically mediated, islet beta cell destruction. This destruction is initiated in genetically predisposed individuals by as yet undefined (environmental or non-genetic) factors. A "crude" immunoassay for islet cell antibodies in combination with serial endocrinologic testing has enabled us to define the chronology of this beta cell destructive process. The fundamental aim of the proposed research is to further characterize the natural history and mechanism of autoimmune beta cell destruction. In particular, the nature and antigen-specific regulation of this autoimmune response will be evaluated. Clinical studies to systematically examine the natural history of beta cell destruction in human type I diabetes will include: 1) identification of subjects very early during the pre-clinical phase of type I diabetes through large scale longitudinal screening of genetically predisposed individuals (first degree relatives) for the presence of circulating islet cell antibodies/antigens, (2) serial assessments of beta cell function during the preclinical phase, and 3) study of potential non-genetic factors which initiate the autoimmune response and influence the course of beta cell destruction leading to overt insulin-dependent diabetes. Basic investigations to probe the mechanism(s) of beta cell destruction will comprise: 1) establishment of permanent human beta-cell lines through gene transfer and somatic cell fusion, 2) generation of beta cell specific murine and human monoclonal antibodies utilizing hybridoma and related techniques, 3) isolation, purification and characterization of beta cell specific antigens, 4) development of sensitive and specific radioassays for circulating islet cell antibodies and antigens in the sera of type I diabetics, and 5) evaluation of the functional significance of islet cell antibodies and their autoantigens in the process of beta cell destruction. By providing fundamental insights into the cellular and molecular mechanisms involved in the beta cell destructive process, these studies may contribute towards development of prophylactic and therapeutic strategies for the ultimate cure or prevention of type I diabetes. On a broader perspective, these studies will be useful for understanding the immunobiology of autoimmune diseases in general.